The invention concerns esters of polyhydric alcohols of hyaluronic acid resulting from the esterification of such alcohols with two or more carboxy groups of the hyaluronic acid polysaccharide, esters which, due to the presence of bridge bonds between the above carboxy functions of the same or different molecules of hyaluronic acid, may be described by the term "cross-linked". These cross-linked esters may be total or partial and, in the latter, further carboxy functions may be esterified with monohydric or polyhydric alcohols, without the formation of cross-links (ester groups which shall also hereinafter be termed "simple"). In both types of cross-linked partial esters, non-esterified carboxy functions may be free or salified with metals or organic bases.
The invention also concerns the use of new cross-linked hyaluronic esters in the field of biodegradable plastic materials for the preparation of sanitary and surgical articles, in the pharmaceutical and cosmetic fields and, therefore, includes the various articles made with the same in such fields.
The specific use of the new esters may be seen in relation to the degree of cross-link esterification, that is the number of cross-linked groups of carboxy functions esterified with the above polyhydric alcohols, the number of simple esterified groups, and, lastly, also the number of salified groups, this degree of esterification or salification being itself related to the solubility of the product and to its viscous-elastic properties. Thus, for example, the total cross-linked esters are virtually insoluble in aqueous liquids and are very suitable, due to their molecular structure, for use in the making of plastic materials and resins and as additives for these materials. Esters with an average or low degree of esterification and their salts with inorganic or organic bases are more or less soluble in aqueous conditions and are suitable for the preparation of gels which may have many uses, both in cosmetics and pharmacology and in the medical-sanitary field in general.
The application for European patent No. 0 161887 of 3.5.85, published on 21.11.85, contains a description of some cross-linked derivatives of hyaluronic acid obtained by the reaction of epoxy compounds indicated as "polyfunctional". In the above patent publication, the term "polyfunctional epoxy compounds" means hydrocarbons with at least one epoxy function and possibly having also convertible functions in epoxy functions, the cross-linking reaction occurring through the epoxy groups. Of these functions, only the halogens are mentioned in the patent. Of these polyfunctional epoxy compounds only a few examples are mentioned in the above patent application, namely: epichlorohydrin, epibromohydrin, methylepichlorohydrin, methylepibromohydrin, 1,2-bis (2,3-epoxypropoxy)-ethane, 1,4-bis (2,3-epoxypropoxy)-butane, 1,6-bis (2,3-epoxypropoxy)-butane, 1,6-bis (2,3-epoxypropoxy)-hexane and a glycidyl ether of bisphenol A and bisphenol F. The preparation method used in this patent application, which is limited in the claims to the use of a halomethyloxyrane or a bisepoxy-compound, as well as being limited in its possible applications, gives cross-linked esters of hyaluronic acid with a low degree of esterification: in fact, as can be seen from the illustrative Examples of the patent application, a maximum of 4% esterification is reached in the case of reaction with epichlorohydrin (Example 4) to obtain a product with a low degree of solubility.
The present invention makes available a wide assortment of cross-linked esters, including particular esters wherein the ester groups, comprise radicals which are unsubstituted by a hydroxyl (as in the case of products resulting from the reaction of the above epoxides on hyaluronic acid or its salts). Importantly the invention provides mixed esters comprising a mixture of ester groups which are cross-linked and some ester groups which are not cross-linked, wherein the percentage of crosslinking groups may exceed 10% of all of the disaccharide units of hyaluronic acid.
The applications for UK patent No. 2 151 244 A of 13.8.1984, published on 17.7.1985, and the application for German Offenlegungsschrift No. 34 34 082 A1 of 17.9.1984, published on 11.7.1985, contain descriptions of some cross-linked derivatives of hyaluronic acid obtainable by the action on the same of formaldehyde, dimethylolurea, dimethylolethylenurea, a polyaziridine, a polyisocyanate and a divinylsulfone. Such derivatives are insoluble and are proposed, due to their biocompatibility, for in vivo applications in the form of various prosthetic articles, such as cardiac valves, vascular clips, etc., or may be added to the various polymeric materials used to make such articles. The same patents provide for the use of ethyl oxide as an agent to achieve "cross-linking", but the procedure is not illustrated, and neither is the type of product obtained. The structure of other cross-linked derivatives is not specified and no mention is made of the type of bonds forming the cross-linking. In the case of formaldehyde and of the above substituted ureas, this could mean derivatives involving the carboxy groups of hyaluronic acid with a semiacetalic structure, while in other cases it could mean alkylated products of hydroxyls.
It is possible, therefore, to define the main object of the present invention as being the total and partial cross-linked esters of hyaluronic acid with polyhydric alcohols of the aliphatic series. In the partial cross-linked esters, there may be carboxy groups esterified with monohydric or polyhydric alcohols of the aliphatic, alicyclic, araliphatic or heterocyclic series, and in the partial esters there may be nonesterified, salified carboxy groups with inorganic or organic bases, with the exception of cross-linked esters obtained by the action of a halomethyloxyrane or of a bisepoxy-compound on hyaluronic acid.